Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals

Abstract

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

“…These examples feature iron-catalyzed cross-couplings of 1-alkynylcyclopropyl derivatives (Scheme 24 A), [73] iron-catalyzed ring openings/cross-couplings of 2-pyrones (Scheme 24 B), [74] and cross-couplings of glycosyl halides (Scheme 24 C). [75] It is significant that these reactions proceed with traditionally challenging electrophiles with exquisite chemo-, regio-, and diastereoselectivity,t hus providing facile access to complex bioactive products that would be laborious to prepare by other methods. [76] Overall, the examples presented in this Section provide motivation and new outlook for future industrial applications of iron-catalyzed cross-couplings for the sustainable synthesis of bioactive products.…”

Synthesis of Non‐Classical Arylated C‐Saccharides through Nickel/Photoredox Dual Catalysis

“…Noteworthy, good to excellent diastereoselectivity was observed for certain furanosyl units ( 2a , 2d , and 2e ), likely because of steric interactions with the adjacent substituent, an effect observed by Nakamura and coworkers in their recent iron-catalyzed arylation of halosugars. 9 Excellent dr has also been observed in the field of photoredox/Ni catalysis when 2-methylcyclopentyltrifluoroborate was coupled with aryl bromide, affording exclusively the trans product. 20 …”

“…As illustrated in Figure 1, the reaction was remarkably tolerant of substitution in the saccharide scaffold, providing the desired products in moderate to high yields.N otably,g ood to excellent diastereoselectivity was observed for certain furanosyl units (2a, 2d,and 2e), likely because of steric interactions with the adjacent substituent, an effect observed by Nakamura and co-workers in their recent iron-catalyzed arylation of halosugars. [9] Excellent diastereoselectivity was also observed in the field of photoredox/Ni catalysis when 2-methylcyclopentyltrifluoroborate was coupled with aryl bromide,affording exclusively the trans product. [20] Thes teric control at the l-arabinofuranose and dxylofuranose derivatives was made evident when comparing the effect of the vicinal substituent, where small substituents (e.g.,MeO and F, 2b and 2c,respectively) afforded poor d.r.…”

“…This transformation has been achieved in the presence of nickel, 7 cobalt 8 or iron 9 catalysts, affording the desired saccharide derivatives in moderate to good yields. Alternatively, pyranosylstannanes could be coupled with aryl halides in the presence of a palladium catalyst.…”

Eisenkatalysierte Kreuzkupplungen in der Synthese von Pharmazeutika: Streben nach Nachhaltigkeit

“…[73] eisenkatalysierte Ringçffnungen/Kreuzkupplungen von 2-Pyronen (Schema 24 B) [74] und Kreuzkupplungen von Glycoxylhalogeniden (Schema 24 C). [75] Es ist entscheidend, dass diese Reaktionen mit üblicherweise anspruchsvollen Elektrophilen mit sehr guter Chemo-, Regio-und Diastereoselektivität verlaufen und so leichten Zugang zu komplexen bioaktiven Produkten ermçglichen, die mit anderen Methoden schwieriger herzustellen wären. [76] Insgesamt bieten die Beispiele dieses Abschnitts die Motivation und einen neuen Ausblick auf zukünftige industrielle Anwendungen von eisenkatalysierten Kreuzkupplungen füre ine nachhaltige Synthese biologisch aktiver Produkte.…”